1. Field of the Invention
The present invention relates to the field of diagnostic imaging and radiotherapy technology, more specifically, to a series of radioisotope trithiol complexes.
2. Description of Related Art
An underlying theme of nuclear medicine is the radiotracer principle. This principle uses a radiolabeled molecule (radiopharmaceutical) in extremely low concentrations (often μM or less depending on half-life) for imaging and treatment of disease. The use of a trace amount of material avoids toxicological effects often observed at the macroscopic level, and often found in pharmaceuticals. Several FDA approved radiopharmaceuticals are currently in use using this underlying concept.
Utilization of the radioisotopes at trace levels often requires the development of a chelate with high in vivo stability that can be linked to a targeting vector such as a peptide or monoclonal antibody. However, the development of such complexes has been challenging. The radioisotopes are present in low concentrations, often at nanomolar concentrations, making it difficult to create a stable complex. Further all chemical derivatizations, conjugation to targeting vectors, transport and in vivo delivery must occur within the half-life of the radioisotope. Thus, radioisotopes used in such complexes preferably have relatively long half-lives to permit chemical derivatization and linkage to targeting vectors prior to in vivo use. These challenges are not present in macroscopic approaches to chelating the stable isotopes of the radioisotopes.
Radioisotopes of arsenic, 71, 72, 74, 77As′ have relatively long half-lives compared to traditional radionuclides such as 18F, 99mTc, 89Sr, 90Y, 111In and 153Sm. These radioarsenic isotopes have suitable half-lives to permit chemical derivatization and in vivo localization using monoclonal antibodies (mAbs) and proteins for imaging and therapy. Arsenic radioisotopes include the positron emitters, 71As (t1/2 64.8 h, 32%, Eβ+max 2.0 MeV), 72As (t1/2 26.4 h, 88%, Eβ+max 2.5 MeV), 74As (t1/2 17.8 d, 29%, Eβ+max 0.94 MeV), and a beta emitter, 77As (t1/2 38.4 h, 100% 13+, Eβ-max 0.68 MeV), giving them the ability to be used as ‘matched pair’ radioisotopes for positron emission tomography (PET) and radiotherapy. The positron emitters are available through the bombardment of various targets using an accelerator or cyclotron. The beta emitter, 77As, can be produced through the irradiation of an enriched 76Ge target to produce 77Ge (t1/2 11.6 h, 100% β−), which decays to no-carrier added 77As. While several production and separation methods for radioarsenic compounds have been developed, little work in stably complexing radioarsenic has been performed.
Utilization of these radioisotopes of arsenic requires the development of a chelate with high in vivo stability that can be linked to a targeting vector such as a peptide or mAb. A survey of current literature only revealed two attempts at stably complexing no-carrier added arsenic. The first was done by Jahn et al. using an N2S2 monoamine-monoamide (MAMA) chelator, and they concluded that the radioarsenic was quantitatively complexed, which has not been further confirmed. The second was carried out in high yield by Jennewein et al. by directly labeling a sulfhydryl modified mAb using 74177AsI3. It was determined that the sulfhydryl modification caused no inhibition of the immunoreactivity of the mAb and the labeled complex was stable for up to 72 h in fetal bovine serum. In a later publication by Jennewein et al. they utilized this labeled antibody to successfully image subcutaneous Dunning prostate tumors in rats. However, there is a need to develop a stable radioarsenic complex, which employs a stable chelate and provides a simplified route for the direct complex of radioarsenic and other radioisotopes.